Sepsis is a major health problem in high-risk newborn infants in the neonatal intensive care unit (NICU), where it occurs in 25 percent of very low birth weight infants and leads to a more than doubling of mortality and a 50 percent increase in hospital stay. Abnormal heart rate characteristics (HRC) of reduced variability and transient decelerations occur early in the course of neonatal sepsis, and predictive multivariable models for sepsis and death have been developed at one center and validated at another. Our long-term goal is to test the hypothesis that continuous HRC monitoring will improve care of these patients by earlier diagnosis of sepsis and other sub-acute, potentially catastrophic illnesses. We propose to advance toward this objective by completing three research aims. In Aim 1, we will test the hypothesis that incorporating conventional lab tests and clinical findings with HRC will lead to improved predictive models for early diagnosis of late-onset neonatal sepsis. In Aim 2, we will identify mechanism-specific tests and findings, and test the hypothesis that they add information in predictive models of late-onset neonatal sepsis. The clinical research design for these Aims is a derivation of multivariable predictive statistical models from one set of patients followed by a validation phase using clinical data from a second set of patients. In Aim 3, we will develop new mathematical measures that detect abnormal HRC early in the course of late-onset neonatal sepsis, in particular, measures of deceleration characteristics. We feel that HRC monitoring in the NICU is a truly novel approach, and we intend to lead the field in developing predictive algorithms for clinical use in the early diagnosis of neonatal sepsis.